The kidney is a primary target for toxicants including drugs, chemicals and environmental pollutants. In the kidney, the proximal tubule epithelium (PTE) is the most important target for toxicant-induced cell death. The ability of the PTE to express stress proteins in response to chemical damage is a first line defense against toxicants. However, there is little information regarding how stress gene expression functions in cytoprotection in the kidney. Moreover, attempts to modulate the intrinsic stress response as a therapeutic strategy have not been successful. Finally, cells die by either apoptosis or necrosis, thus, the task of understanding how stress genes function in cell protection has become more complex. The continuing long-term goal is to understand how stress genes prevent renal injury and to exploit stress gene activation for clinical benefit. In this continuation application the hypothesis that, "The ER stress response protects against nephrotoxicants, but distinct ER signaling pathways and proteins mediate tolerance to different forms of cell injury" will be tested." The roles of the glucose regulated protein gene grp78, calreticulin and other ER stress genes in pathways, which protect PTE cells from chemical toxicants, will be determined. In-depth structure activity studies to determine the types of injury that ER stress genes will protect against will be carried out. Molecular mechanisms through which ER stress genes produce cellular protection against chemical damage in vitro will be dissected using genetic manipulations. The role of discrete ER signaling pathways in protecting kidney epithelial cells from apoptosis and necrosis in vivo and in vitro will also be elucidated. These studies will provide new information on the role of stress genes in mechanisms of kidney cell death. The long-term goal is to develop therapeutic strategies to provide better protection against kidney damage. An initial prototype compound that is effective in inducing stress response genes and tolerance to injury in vitro and in vivo has been developed as part of the application.